Fatty acid amides are biologically active lipids that mediate signaling associated with diverse processes such as sleep, pain, memory, and feeding. Classes of biologically active endogenous fatty acid amides include N-acylethanolamines (e.g., anandamide), N-acyl amino acids (e.g., N-acyl taurine), and fatty acid primary amides (e.g., oleamide). Anandamide activates cannabinoid receptors and elevated anandamide levels are observed in pain-sensitive areas of the brain in response to pain stimulation (Walter et al., 1999 Proc Natl Acad Sci USA. 96(21): 12198-12203). N-acyl amino acids have been shown to suppress pain and activate signaling through transient receptor potential (TRP) calcium channels (Huang et al., 2001 276(46):42639-44; Saghatelian et al., 2006 Biochem. 45(30):9007-15). Oleamide accumulates in the cerebrospinal fluid of sleep deprived animals, and administration of exogenous oleamide has sleep-inducing effects (Mendelson and Basile, 2001 Neuropsychopharmacol. 25(S5):S36-S39).
The biological activity of fatty acid amides is regulated by hydrolysis in vivo. Fatty acid amide hydrolase 1 (also known as FAAH or FAAH1) hydrolyzes N-acyl ethanolamines such as anandamide and N-acyl taurines Inhibition or complete disruption of FAAH1 signaling in rodents leads to elevated levels of endogenous fatty acid amides and correlates with reduced sensitivity to pain, and benzodiazepine-like anti-anxiety behaviors (Cravatt et al., 2001 Proc. Natl. Acad. Sci. U.S.A. 98(16): 9371-6; Kathuria et al., 2003 Nat. Med. 9(1):76-81). Primates, marsupials, and other species have a gene encoding a second fatty acid amide hydrolase, FAAH2 (Wei et al., 2006 J. Biol. Chem. 281(48):36569-36578). FAAH2 and FAAH1 have distinct but overlapping substrate specificities. While both enzymes hydrolyze fatty acid amides, FAAH2 exhibits a preference for mono-unsaturated acyl chains whereas FAAH1 prefers polyunsaturated acyl chains. FAAH2 hydrolyzes anandamide at a ˜50 fold lower rate than FAAH1. Both enzymes hydrolyze oleamide at an equivalent rate, and both enzymes are susceptible to inhibition by URB597, a carbamate inhibitor, and OL-135, an α-ketoheterocycle.